H. pylori colonization increases the risk for gastric adenocarcinoma yet only a fraction of infected persons ever develop cancer. H. pylori strains that contain the cag pathogenicity island (cag+) augment the risk for severe gastritis and gastric cancer, and we have shown that cag genes are required for the development of inflammation in a rodent model of H. pylori-induced gastric cancer. Our data also demonstrate that cag genes are necessary for induction of proinflammatory cytokine release and apoptosis in gastric epithelial cells in vitro, events mediated by NF-(B and/or mitogen-activated protein kinases (MAPK). In vivo, however, heterogeneity exists among apoptosis scores within infected populations, and one explanation for such variability is H. pylori genetic diversity. Gastric epithelial cell proliferation is higher but apoptotic indices are lower among persons colonized with cag+ compared to cag- strains or uninfected persons, and reduced rates of cell loss, when accompanied by hyperproliferation, may heighten retention of mutagenized cells, which could predispose towards malignancy. One host effector that may influence carcinogenic pathways associated with H. pylori is matrilysin, a matrix metalloproteinase that enhances tumor formation, and is over-expressed in premalignant and malignant lesions within H. pylon-infected human mucosa. Constitutive expression of matrilysin selects for cells with a reduced sensitivity to apoptosis, and we now show that matrilysin is detected exclusively in human mucosa colonized by cag+ strains, and these strains selectively induce matrilysin in vitro through cag-mediated activation of NF-(B and MAPK. Another host pathway through which inflammatory mediators may influence pathogenesis is PPAR(, a nuclear transcription factor. Our data now show that PPAR( activation inhibits H. pylori-induced NF-(B signaling in vitro, and attenuates inflammation and injury in rodent models of H. pylori-induced gastritis. [unreadable] Our hypothesis is that strain-selective activation of NF-(B and/or MAPK by cag+ strains regulates matrilysin expression which may contribute to the augmentation in carcinogenic risk associated with these strains by attenuatinq apoptosis within colonized mucosa, and that PPAR( activation suppresses phenotypes related to carcinogenesis by inhibiting H. pylori-induced NF-(B-mediated responses in gastric epithelial cells. To address this, our specific aims are: 1) To determine the effects of H. pylori and mutant strains on matrilysin-dependent cellular responses related to carcinogenesis in vitro and in matrilysin deficient mice; 2) To identify targets of PPAR( that suppress H. pylori-induced epithelial responses associated with oncogenesis; and 3) To determine the role of PPAR( in regulating inflammatory and injury responses to H. pylori using in vivo models of PPAR( pharmacologic activation and genetic deficiency. Studies of these variables in vitro and in animal systems that reflect pathogenesis in humans will not only improve our understanding of H. pylori-induced carcinogenesis and facilitate identification of potential therapeutic targets, but may also provide insights into other malignancies that arise within the context of inflammatory states. [unreadable] [unreadable]